This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cysteine proteases are present in nearly all groups of eukaryotes and play vital roles in a wide range of biological processes and diseases, including antigen processing, bacterial infection, arthritis, osteoporosis, Alzheimer?s disease and cancer cell invasion. Several cysteine proteases of the papain superfamily are critical to the life-cycle progression of many pathogenic protozoa and therefore they represent potential targets for selective inhibitor design. It has also been determined that members of this same class of enzyme are required for human allergic and asthmatic response to the common house dust mite. High-resolution structural studies have provided valuable information for the design of anti-parasitic therapeutics that selectively regulate the cysteine protease cruzain, a key enzyme in the lifecycle of T. cruzi, the causative agent of Chagas? disease. The studies detailed in this program will expand our understanding and ability to regulate several new protease targets indicated in a variety of parasitic infections as well as proteases of dust mite allergy induced asthma.